A novel approach for diagnosis and newborn screening for 22q11 deletion syndrome

22q11 缺失综合征诊断和新生儿筛查的新方法

• 批准号: 7921767
• 负责人: LISA J. KOBRYNSKI
• 金额: $ 10.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921767
• 关键词: 22q; 22q11; 22q11 Deletion Syndrome; 22q11.2; Adolescence; Affect; Biological Assay; Birth; Blood; Childhood; Chromosomes, Human, Pair 22; Complex; Congenital Heart Defects; DNA; DNA Probes; Detection; Development; DiGeorge Syndrome; Diagnosis; Disease; Dyes; Early treatment; Fluorescent in Situ Hybridization; Frequencies; Goals; Hypoparathyroidism; Incidence; Individual; Label; Live Birth; Measures; Medical; Neonatal Screening; Newborn Infant; Patients; Population; Relative (related person); Running; Sampling; Schizophrenia; Schools; Screening procedure; Sensitivity and Specificity; Shprintzen syndrome; Speech Delay; Spottings; Syndrome; Testing; Time; Whole Blood; case control; cohort; microdeletion; novel strategies; population based; public health relevance; thymic aplasia

DESCRIPTION (provided by applicant): Digeorge syndrome/Velocardiofacial syndrome/22q11.2 deletion syndrome is a complex disorder due to a microdeletion of 1.5 or 3 Mb on the long arm of chromosome 22. This is one of the most common deletion syndromes affecting approximately 1:3000 live births. Affected individuals may be diagnosed shortly after birth due to the presence of a congenital heart defect. However, those individuals without a heart defect usually have a significant lag in time before diagnosis, despite multiple medical problems. Some of the associated conditions such as hypoparathyroidism or thymic aplasia require immediate therapy soon after birth. Other conditions such as the speech delay, school difficulties or the development of schizophrenia have their onset in childhood and adolescence, but would benefit from early recognition and treatment. Currently this microdeletion is detected through the use of fluorescent in situ hybridization demonstrating a hemizygous deletion on chromosome 22. While this assay is commercially available, it is expensive and time consuming to perform and requires a sample of whole blood. This makes the assay unsuitable for use in population screening. The specific aims of this proposal are to develop an assay using a DNA probe labeled with an infrared dye to detect a 2 fold copy difference in normal controls versus patients with the deletion using DNA extracted from dried blood spots. This assay could be used for diagnosis and as a population based screening test for this disorder. The sensitivity and specificity and reliability of the assay will be measured using a small cohort of known controls and affected patients (confirmed by FISH) with repeated measures, then assessed for reliability in a larger cohort of cases and controls and ultimately in an unknown population sample using newborn dried blood spots. The goal of this project is to develop an assay that is quick, sensitive, specific and can be run in a semiautomated fashion allowing for high throughput population screening. PUBLIC HEALTH RELEVANCE: Given the frequency of the 22q11 disorder, the relative complexity and the need for early intervention routine newborn screening for 22q11 Deletion syndrome is indicated. The high incidence of this disorder, along with the need for early intervention, makes 22q11.2 deletion syndrome a good candidate for newborn screening.

描述（由申请人提供）：Digeorge综合征/速食综合征/22Q11.2缺失综合征是一种复杂的疾病，这是由于22染色体的长臂上的微缺失1.5或3 MB。由于存在先天性心脏缺陷，可能会在出生后不久被诊断出受影响的个体。但是，尽管有多个医疗问题，但没有心脏缺陷的那些人通常在诊断前的时间有明显的滞后。一些相关的疾病，例如甲状腺功能减退症或胸腺激素，需要在出生后立即立即治疗。其他条件，例如言语延迟，学校困难或精神分裂症的发展，它们在童年和青春期都会发作，但会受益于早期认可和治疗。当前，通过使用荧光原位杂交检测到这种微骨骼，该杂交表明染色体上的半合基缺失。虽然该测定法在市售上可获得，但既昂贵又耗时，并且需要耗时，并且需要全血样。这使得该测定不适合在人群筛查中使用。该提案的具体目的是使用用红外染料标记的DNA探针开发一种测定法，以检测正常对照组中的2倍拷贝差异与使用从干血点提取的DNA的患者相比，从而检测出2倍的副本差异。该测定法可用于诊断，并作为该疾病的基于人群的筛查测试。测定的敏感性，特异性和可靠性将使用一小部分已知对照组和具有重复措施的患者（通过鱼类确认）进行测量，然后在较大的病例和对照组中评估可靠性，并最终在未知的人群样本中使用新出生的干燥血液斑点进行评估。该项目的目的是开发一种快速，敏感，具体的测定法，并且可以半肢体的方式运行，从而可以进行高吞吐量筛查。公共卫生相关性：鉴于22q11疾病的频率，相对复杂性和对22q11缺失综合征的新生儿筛查的相对复杂性和需求。这种疾病的高发病率以及对早期干预的需求，使22q11.2缺失综合征成为新生儿筛查的良好候选者。